KR20210005664A - Topical pharmaceutical composition for the treatment of anal fissure and hemorrhoids - Google Patents

Abstract

The present invention relates to a topical pharmaceutical composition for use in the anal region of the anal fissure and hemorrhoid, including the postoperative period of hemorrhoidectomy. Such pharmaceutical compositions include an anal dilator, a mucoadhesive polymer and a non-aqueous vehicle. In addition, a method of preparing the pharmaceutical composition of the present invention is described.

Description

Topical pharmaceutical composition for the treatment of anal fissure and hemorrhoids

The present invention relates to a topical pharmaceutical composition for use in the anal region of the anal fissure and hemorrhoid, including the postoperative period of hemorrhoidectomy.

Anal fissure is an anorectal disease that affects at least 11% of the world's population. This condition is characterized by lacerations or ulcerative lesions on the anal canal or the skin that borders the anus, often resulting in spasm and bleeding during excretion. In addition to spasms and bleeding in the anal area, its main symptoms are pain during defecation, pruritus, irritation of the skin in the anal area, and rectal prolapse in some patients. This disease also affects men and women of all ages, the most frequent causes of which are diet, irritable bowel disease, Crohn's disease and local trauma.

Anal fissure treatment generally involves the application of an anesthetic for pain management, the use of a treatment pad, and waiting for wound healing (which usually occurs within 6 to 8 weeks after the start of treatment). In some cases, depending on the severity of the wound, the depth of the wound, and the hemorrhagic degree, the patient may undergo surgery to close the wound.

Anal fissure is a disease separate from hemorrhoids and consists of dilation of the submucosal anal rectal vein due to elevated venous pressure in the hemorrhoidal plexus. External hemorrhoids develop below the parietal line and are covered by scaly or cutaneous epithelium. On the other hand, the internal hemorrhoids are located in the internal hemorrhoidal plexus above the parietal line and are covered by a columnar mucosa or transitional epithelium. The main symptoms presented by patients with hemorrhoidal disease are bleeding, prolapse of hemorrhoidal nipples, anal pain or discomfort, acute inflammation (thrombosis with or without signs of phlebitis), irritation or perianal dermatitis. , And a feeling of incomplete rectal emptying after defecation.

Typically, treatment of hemorrhoids involves a change in the patient's eating habits, proper hygiene of the area, and the use of topical agents such as disinfectants, vasodilators and anesthetics.

Other treatment methods common to hemorrhoids and anal fissures are described below. Application of topical corticosteroids can reduce local inflammation. However, drugs in this group have little efficacy in the treatment of the disease (there is no clinical evidence demonstrating a reduction in swelling, bleeding or hemorrhoidal prolapse due to the use of these drugs). However, topical corticosteroids have the risk of infection and skin atrophy as side effects.

Botulinum toxin has already been used experimentally for the treatment of anal fissures. Laboratory studies have identified that their efficacy is similar to that of nitrate studies. Despite the lower rate of side effects, botulinum toxin presents a lower healing rate and a greater recurrence rate than surgical sphincterotomy. The cost of treatment is high, and the dosages and techniques used are not standardized. Prolonged use of botulinum toxin can lead to the probability of infection, local hematoma, hemorrhoidal thrombosis, and temporary incontinence.

Lidocaine, cinchocaine, and other amide-type anesthetics have been used topically for symptomatic enhancement in patients with anal fissures. Anesthetics of the amide group are more common than other groups of anesthetics for topical application in this area, as these anesthetics do not cause allergic reactions and sensitization like ester-type anesthetics that are metabolized to methylparabenzoic acid.

The use of betanchol for the treatment of fissures provides a good clinical response and the incidence of complications and side effects is low. However, in a laboratory study comparing betanchol and diltiazem, diltiazem was found to support a successful clinical response by a greater time between treatment of anal fissures and hemorrhoids and a lower incidence of recurrence.

Some calcium channel blockers (such as diltiazem and nifedipine) reduce the resting pressure of the sphincter in the treatment of anal fissures and in the postoperative period of hemorrhoidectomy, and facilitate wound healing in the inner region of the anal cavity and at the border. Has been used by Document published in November 2013 [Dr. Carlos Walter Sobrado of the Faculty of Medicine of the University of Sao Paulo, Treatment of Anorectal Diseases] found that topical 0.2% nifedipine achieved a cure rate of 80% to 90%, while 2% topical diltiazem in ointment. It is stated that use has achieved a cure rate of 75%. [E. A. Carapeti, et al. Topical Diltiazem and Bethanechol Decrease Anal Sphincter Pressure Without Side Effects, 1999] disclosed the use of diltiazem for topical and oral application in the treatment of anal fissures, and the topical use of ingredients at a concentration of 2% was disclosed. Indicates preference for.

In general, the aforementioned active agents are available in the form of individualized ointments consisting of petrolatum preparations and additional elements such as aloe vera, astringents and disinfectants, which often do not resolve the anal fissure disease in an effective and sustained manner. Temporarily inhibits the symptoms of

As a pharmacological excipient best used in the preparation of topical formulations for the treatment of anal fissures, petrolatum (VASELINE®, petrolatum) causes serious defects in the treatment of fissures, as described below. Vaseline, despite its good diffusivity, does not have good adhesion to human skin, it often falls off (especially at temperatures above 35°C), contaminates the patient's clothing, and is the active ingredient of the drug for a therapeutically sufficient time. Do not keep in contact with human skin.

Moreover, the need to reapply creams, ointments and gels for the treatment of anal fissures and hemorrhoids is a common complaint among rectal practitioners.

If treatment with more than one active ingredient is required, it is advantageous to have the active ingredient in the same formulation for a variety of reasons: (i) In case of acquiring different medicaments for different active agents, the patient may apply a double application of the product in their anal area. Suffer from discomfort (discomfort that worsens at the same rate of sensitivity of the fissure); (ii) Upon application of the product with a separate active agent, the patient initially deposits a layer of the product containing the first active agent on the affected area, and then a second layer with the second active agent on the first layer. (Obviously, in this situation, the active agent of the second layer may exhibit delayed absorption by human skin due to the presence of the first layer); (iii) By combining two separate active agents with conventional excipients, the end user cannot predict the interference of one agent in the other, for example the active agent interacting with another agent.

There is a need for topical formulations for use in anal fissures and hemorrhoids, comprising at least one active ingredient that inhibits pain and at least one active ingredient for relaxing anal muscle tension, wherein the two principles are stable. And combined in the appropriate formulation. Desirably, the formulation will alleviate the discomfort and inefficiency of petrolatum, for example it will not drop out after application, provide greater adhesion to the patient during treatment, and provide stability to the active agent.

An object of the present invention is a formulation that allows a combination of two or more effective drugs for the treatment of anal fissures, hemorrhoids and the treatment of the anal area. In certain embodiments, such formulations contain functional excipients for diffusivity, adhesion and viscosity suitable for application of topical agents in the anal area. In certain embodiments, the formulation can be effectively applied once daily.

Gels have been found to overcome some of the drawbacks of ointment formulations (for example those containing components such as liquid and/or solid petrolatum). A gel is a semi-rigid system consisting of a three-dimensional network in which particles or macromolecules solvated by a dispersed phase are interlaced. Gels are classified as hydrogels when the continuous phase is aqueous and organic gels when the continuous phase is an organic solvent.

Furthermore, it has been found that organic gels have improved properties over hydrogels in relation to the activators considered in the present invention. The water in the gel formulation is an undesirable change, such as: (i) the creation of an environment conducive to the growth of microorganisms that rely on water for survival; (ii) direct chemical changes in the active agent by reactions such as hydrolysis caused by the medium; And (iii) physical instability of the formulation.

The present invention comprises a topical pharmaceutical composition suitable for application to the anal area, the pharmaceutical composition comprising: a topical local anesthetic, an anal dilator (with an "active ingredient"), preferably delivered in a single organic gel. , Non-aqueous vehicles, and mucoadhesive polymers. In certain embodiments, the anal extender is the sole active ingredient. The present invention also includes a method for preparing a topical pharmaceutical composition, the method comprising the following sequential steps:

Step 1: adding the non-aqueous vehicle in a suitable container and heating to 20° C. to 50° C.;

Step 2: adding the active ingredient(s) and shaking;

Step 3: cooling the solution to 20°C to 40°C, if necessary, and leaving it to stand;

Step 4: adding a polymer, such as a mucoadhesive polymer, together with a non-aqueous vehicle; And

Step 5: Optionally add an antioxidant to the product of step 4 above, and shake until completely homogeneous.

The present invention includes topical pharmaceutical compositions suitable for application to the anal area, wherein the pharmaceutical composition comprises the following elements: a mucoadhesive polymer, optionally a local anesthetic (for example for topical use), an anal dilator, and a vehicle. Include. Typically, the vehicle is non-aqueous. "Anal dilator" means any vasodilator that can be applied through topical use and has a local effect on the anal sphincter, such as "nitrates and nitrites" (eg nitroglycerin/glyceryl trinitrate (GTN), Isosorbide dinitrate, isosorbide mononitrate, butyl nitrite, amyl nitrite) and “calcium channel blockers” (eg amlodipine, diltiazem, felodipine, isradipine) (isradipine), nicardipine, nifedipine, nisoldipine, verapamil).

“Non-aqueous vehicle” refers to a formulation that serves to form, dissolve, suspend or mix homogeneously with other ingredients, with other ingredients, to facilitate their administration or to make it possible to prepare pharmaceutical forms. Refers to a component; The component is substantially free of water (eg less than 1% v/v, less than 0.5% v/v or even less than 0.1% v/v water). Exemplary compounds for non-aqueous vehicles are caprylic capric triglyceride oil, diethylene glycol monoethyl ether, medium chain mono-diglyceride, castor oil, polyethylene glycol (PEG, e.g. PEG 400), Mineral oil, coconut oil, oleic acid, medium chain triglyceride, caprylocaproyl macrogol-8 glyceride, propylene glycol, glycerin and polyethylene glycol derivatives alone or in combination. Preferred combinations of compounds for vehicle include propylene glycol, polyethylene glycol 400, diethylene glycol monoethyl ether and caprylocaproyl macrogol-8 glyceride.

Typically, the non-aqueous vehicle used in the formulation of the present invention is propylene glycol and/or polyethylene glycol and/or diethylene glycol monoethyl ether and/or caprylo-caproyl macrogol-8 glyceride, which Often present at a rate of 5.0% w/w to 90.0% w/w, such as 70% w/w to 90% w/w, or 80% w/w to 90% w/w. In certain embodiments, the non-aqueous vehicle comprises 70% w/w to 90% w/w of the total composition, wherein 10% w/w to 20% w/w (14% w/w to 18% w /w) of PEG 400, 25% w/w to 35% w/w (30% w/w to 35% w/w) of propylene glycol, 20% w/w to 30% w/w (20% w /w to 25% w/w) of diethylene glycol monoethyl ether and 10% w/w to 20% w/w (14% w/w to 18% w/w) of caprylocaproyl macrogol-8 Glycerides are present.

More preferably, the present invention comprises a formulation consisting of a mucoadhesive platform, a non-aqueous vehicle, diltiazem hydrochloride as an anal expander, and lidocaine (e.g. hydrochloride salt) as a local anesthetic. It consists of an organic gel for the treatment of fissures and/or hemorrhoids.

“Organic gel” is a type of gel consisting of a gelling agent dispersed in an organic solvent (eg a non-aqueous vehicle).

In one embodiment, diltiazem hydrochloride is an anal dilator, as such calcium channel blockers have been shown to be effective in reducing the resting pressure of the anal sphincter. Diltiazem hydrochloride has already shown good results in the treatment of chronic anal fissures and hemorrhoids, including the postoperative period after hemorrhoidectomy. A study comparing the use of oral diltiazem and topical diltiazem in lowering maximal anal pressure revealed that topical diltiazem was more effective, had fewer side effects, and had a cure rate similar to that found with topical nitroglycerin. I put it out.

In certain embodiments, diltiazem is at a concentration of 0.1% to 10%, such as 0.5% to 5%, especially 1% to 3%, more particularly 1% to 2% (e.g. 1%, 2%). exist.

In certain embodiments, the lidocaine hydrochloride or lidocaine base is an anesthetic.

Typically, the concentrations of the two active agents in the formulations of the present invention are 0.5% w/w to 5% w/w for lidocaine hydrochloride or lidocaine base; For diltiazem hydrochloride, it is 0.1% w/w to 10% w/w. The formulation may also contain a mucoadhesive polymer: hydroxypropylmethylcellulose and/or sodium alginate and/or hydroxyethylcellulose, and/or hydroxypropylcellulose in a ratio of 0.1% w/w to 10% w/w. Can be included as.

In addition to the combination of two above-mentioned active agents in a single pharmaceutical composition, the present invention also provides a placement of such active agents in the form of gels with suitable viscosity, diffusivity and adhesion, which are encountered when using petrolatum. Solve the problems that are thrown.

Bioadhesion is an interfacial phenomenon in which at least one of the two substances is of biological origin and these two substances are fixed together for an extended period by an interfacial force. The bond can be between an artificial material and a biological substrate, such as an adhesion between a polymer and a biofilm. Adhesion can be defined as a bond created by contact between a pressure sensitive adhesive and a surface.

Mucoadhesion is a property resulting from the use of bioadhesive polymers that have the ability to bind to biological substrates by binding to mucosal layers or to cell membranes. This trait allows an extended residence time of the formulation at the site of action or adsorption, thereby enhancing contact of the drug with the skin and/or mucosal epithelial wall. Preferably, the mucoadhesive polymer used in the present invention has the ability to increase the residence time with both the skin and the anal mucosa.

Some examples of mucoadhesive polymers include cellulose (e.g. methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium), carbomer, polyethylene glycol, polycarbophil , Polyhydroxyethyl methacrylate, poloxamer, ethylene polyoxide, polyvinylpyrrolidone (povidone), vinyl, polyvinyl alcohol, polyacrylic acid derivatives, pyroxylin, hyaluronic acid, sodium and/or calcium algi It is a derivative of nate, polysaccharide, acacia, agar, pectin, tragacanth, carrageenan, polypeptide, casein, gelatin, karaya gum, guar gum, xanthan gum, pectin and chitosan. Particularly suitable mucoadhesive polymers include hydroxyethylcellulose, hydroxypropylcellulose, sodium alginate and/or hydroxypropylmethylcellulose.

Hydroxypropylmethylcellulose (HPMC) is insoluble, especially in hot water, chloroform, ethanol (95%) and ether, but forms a viscous colloidal solution in a mixture of ethanol and dichloromethane, a mixture of methanol and dichloromethane, and a mixture of water and alcohol. Is a nonionic, cold water soluble, hydrophilic polymer. Some degree of hydroxypropylmethylcellulose is soluble in aqueous solutions of acetone, mixtures of dichloromethane and propan-2-ol, and other organic solvents. HPMC exerts some buffering capacity and can create a pH-independent system. Among the various types of HPMC, the most widely used to make swellable matrix systems are those with high viscosity grades-HPMC 2208, HPMC 2906 and HPMC 2910 according to the specifications of USP XXV/NF XX.

Hydroxyethylcellulose (HEC) is a nonionic ether or cellulose pulp obtained from the processing of cellulose pulp, soluble in water at room temperature, and used as a general purpose thickener. Hydroxyethylcellulose is biodegradable, physiologically inert, and forms hydrocolloids for various applications in industry. Hydroxyethylcellulose is soluble in both hot and cold water, forming a transparent and uniform solution. Hydroxyethylcellulose is practically insoluble in acetone, ethanol (95%), ether, toluene and most other organic solvents. In some polar solvents such as glycols, hydroxyethylcellulose is also soluble or partially soluble. The aqueous solution of HEC is relatively stable without effectively changing the viscosity at pH 2-12. Hydroxyethylcellulose solutions are less stable with hydrolysis occurring below pH 5.0. At high pH, oxidation can occur. Hydroxyethylcellulose is treated by enzymatic digestion, resulting in a loss of the viscosity of the solution. The enzymes that catalyze this degradation are produced by many bacteria and fungi present in the environment. Therefore, during prolonged storage of such excipients, an antimicrobial preservative must be added to the aqueous solution. These polymers can be used with a wide variety of water soluble antimicrobial preservatives. However, sodium pentachlorophenate exerts an immediate decrease in viscosity when added in HEC solution.

Hydroxypropylcellulose (HPC) is a nonionic, partially substituted poly(hydroxypropyl) cellulose ether that is compatible with cationic surfactants. HPC is very soluble in water below 38° C., forming a clear colloidal solution. In hot water, it is insoluble and precipitates as swollen flakes at temperatures between 40° C. and 45° C. It is soluble in some polar solvents such as short chain alcohols (ethanol, isopropyl alcohol, etc.) and glycols such as propylene glycol, but insoluble in glycerol. It is also insoluble in aliphatic hydrocarbons such as oils and aromatic hydrocarbons. It is insoluble with methylparaben and propylparaben.

Typically, hydroxypropylmethylcellulose and/or hydroxyethylcellulose and/or hydroxypropylcellulose are combined in a ratio of 0.1 to 10% w/w to provide organogel performance.

Sodium alginate is a further suitable mucoadhesive polymer. Alginate is a linear copolymer consisting of α-L-guluronic acid and β-D-mannuronic acid with 1-4 linkages. Substances vary widely in terms of their ratio between the mannuronic acid (M) and guluronic acid (G) residues, as well as their sequence structure and degree of polymerization. In this way, the material can present a block consisting of an alternating sequence of MG residues and two or more residues M or G. Sodium alginate is slightly soluble in water, forming a viscous colloidal solution. It is practically insoluble in alcohol (95%), ether, chloroform, and alcohol/water mixtures, with the ethanol content above 30% by weight. In addition, it is actually insoluble in other organic solvents and acidified aqueous solutions with a pH of less than 3. The characteristics of the gel depend on the M/G ratio and the number of cross-links between the polymer chains. Gels are formed in the presence of divalent cations such as Ca ²⁺ or Mg ^{2+ and in} the presence of a guluronic acid residue sequence.

In one example, the formulation of the present invention comprises 0.5-10% w/w of hydroxypropylcellulose (HPC). In another example, sodium alginate and/or hydroxyethylcellulose is present at 0.5-10% w/w.

In another embodiment of the present invention, skin healing aids are used in the manufacture of pharmaceutical compositions. Although this element is not essential for wound healing, its use can aid in tissue repair, promoting faster healing with better results. Some examples of skin healing aids are papain, D-panthenol, propolis, sunflower oil, calcium alginate, grapeseed oil, hyaluronic acid, chamomile, or Calendula officinalis . In certain embodiments, the skin healing aid is D-panthenol used, for example, in a ratio of 0.5 to 5% w/w.

The formulations of the present invention may also contain one or more antioxidants. Antioxidants that may be used include tocopherol in the alpha form (0.01 to 1.0% w/w), tocopherol in the gamma and beta forms (0.01 to 1.0% w/w); Ascorbic acid (0.01 to 1.0% w/w); Citric acid monohydrate (0.01 to 1.0% w/w), ascorbyl palmitate (0.01 to 1.0% w/w); Butylated hydroxytoluene (0.01 to 1.0% w/w); Butylated hydroxyanisole (0.01 to 1.0% w/w); Erysorbic acid (0.01 to 1.0% w/w); Fumaric acid (0.01 to 1.0% w/w); Malic acid (0.01 to 1.0% w/w); Methionine (0.01 to 1.0% w/w), monothioglycerol (0.01 to 1.0% w/w); Metabisulfite and sodium bisulfite (0.01 to 1.0% w/w); Propionic acid propylgallate (0.01 to 1.0% w/w); Sodium ascorbate (0.01 to 1.0% w/w); Sodium formaldehyde sulfoxylate (0.01 to 1.0% w/w); Sodium sulfite (0.01 to 1.0% w/w); Sodium thiosulfate (0.01 to 1.0% w/w); Dioxide sulfur (0.01 to 1.0% w/w); Polyethylene glycol succinate of thymol and vitamin E (0.01 to 1.0% w/w).

Non-aqueous vehicles aim to promote dissolution and increase solubility of a given active, and in certain embodiments, improve the dermal and transdermal administration of the drug. The mucoadhesive polymer dispersed in the vehicle in question forms an organic gel. Organogels are a specific type of gel in which the polymer swells and retains the organic solvent in a three-dimensional network. In this respect, some of the advantages of using a drug given in the form of an organogel may be delivery of the drug in a manner directed towards the site of action, longer duration of action, improved dermal and transdermal administration, ease of administration, and non-invasive. have. Another advantage of organogels is that because of their pharmaceutical form adhesion to the skin, organogels are maintained for a relatively long period of time before being washed, and contact typically occurs in a non-irritating manner.

Although the active agents of lidocaine hydrochloride (as anesthetics) and diltiazem (as an analgesic) are the preferred actives used by the present invention, other anesthetics and extenders may be used in place of these drugs.

Substitutes for lidocaine are mepivacaine, etidocaine, lidocaine base, prilocaine, bupivacaine, procaine, chlorprocaine. (procaine), ropivacaine, tetracaine (tetracaine), cocaine, amethocaine (ametocaine) and cinchocaine (cinchocaine). Since the ester group anesthetic is metabolized to methylparabenzoic acid, which can lead to a higher incidence of irritation and allergic reactions, it is preferable to use an amide group anesthetic for the ester group anesthetic.

Dihydropyridine instead of diltiazem (e.g. nifedipine, felodipine, amlodipine, lacidipine), phenylalkylamine (verapamil), benzodiazepine , And tetralol (mebefradil) may be a drug belonging to the family (mebefradil). Some examples of extenders that do not belong to the class of calcium channel blockers that can be applied to the present invention are topical nitrates, muscarinic agonists, agonists and adrenaline antagonists (indoramine).

Furthermore, it is possible to include aloe vera in the formulation of the present invention. This component simultaneously acts as a moisturizer, astringent, emollient, anti-inflammatory, analgesic, and skin protectant against UV rays, and an immunostimulant.

Manufacture process:

The process for preparing the pharmaceutical composition of the present invention preferably comprises the following sequential steps:

Step 1: adding the non-aqueous vehicle to a suitable container and heating to 20° C. to 50° C.;

Step 2: adding the active ingredients (eg, diltiazem and lidocaine hydrochloride) and shaking;

Step 3: cooling the solution to 20° C. to 40° C. and, if necessary, leaving it on;

Step 4: In another container, adding a polymer, such as a mucoadhesive polymer, to the non-aqueous vehicle and stirring until completely dispersed;

Step 5: optionally adding a healing aid with the product of step 4 above;

Step 6: Optionally add an antioxidant to the product of Step 5, and shake until completely homogeneous;

Step 7: Pour the product of step 3 into the product of step 6 and stir until completely homogeneous.

Certain compositions include the following components.

agent Amount for 1 gram (g) % Lidocaine hydrochloride 0.02 2.0 Diltiazem hydrochloride 0.02 2.0 Hydroxypropylcellulose 0.04 4.0 Polyethylene glycol 400 0.16 16.0 Propylene glycol 0.32 32.0 D-panthenol 0.05 5.0 Diethylene glycol monoethyl ether (Transcutol P) 0.2296 22.96 Alpha-tocopherol 0.0005 0.05 Caprylocaproyl Macrogol-8 Glyceride (Labrasol) 0.16 16.0

Claims (35)

As a topical pharmaceutical composition,
Mucoadhesive polymer, and
Anal dilator
A pharmaceutical composition comprising in a non-aqueous vehicle. The method of claim 1,
The composition is a semi-solid preparation selected from ointments, creams, gels, organic gels and colloids, pharmaceutical compositions. The method of claim 2,
The composition is an organic gel, pharmaceutical composition. The method according to any one of claims 1 to 3,
The pharmaceutical composition further comprising a local anesthetic. The method of claim 4,
The local anesthetic agents mepivacaine, etidocaine, lidocaine base, lidocaine hydrochloride, prilocaine, bupivacaine, procaine, chlor Procaine (chlorprocaine), ropivacaine (ropivacaine), tetracaine (tetracaine), cocaine, amethocaine (amethocaine) and at least one of cinchocaine (cinchocaine), pharmaceutical composition. The method of claim 5,
The local anesthetic is an amide anesthetic, a pharmaceutical composition. The method of claim 6,
The local anesthetic agent is etidocaine, pharmaceutical composition. The method of claim 6,
The local anesthetic is lidocaine, pharmaceutical composition. The method of claim 8,
The composition comprises 0.5% w/w to 5% w/w of lidocaine hydrochloride. The method according to any one of claims 1 to 9,
The anal expander is a calcium channel blocker, pharmaceutical composition. The method of claim 10,
The calcium channel blockers are diltiazem, nifedipine, felodipine, amlodipine, lacidipine, verapamil, indoramine and mebepradil. mebefradil) of one or more, a pharmaceutical composition. The method of claim 11,
The calcium channel blocker is nifedipine, pharmaceutical composition. The method of claim 11,
The calcium channel blocker is diltiazem, pharmaceutical composition. The method of claim 13,
The composition comprises 0.1% w / w to 10% w / w of diltiazem, pharmaceutical composition. The method according to any one of claims 1 to 14,
The pharmaceutical composition, wherein the local local anesthetic and the anal extender are dissolved in one or more organic solvents, and the mucoadhesive polymer is dispersed in the organic solvent. The method according to any one of claims 1 to 15,
The mucoadhesive polymer is derived from cellulose, a pharmaceutical composition. The method of claim 16,
The mucoadhesive polymer comprises one or more of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, hydroxyethylcellulose, ethylcellulose, and sodium carboxymethylcellulose, pharmaceutical composition. The method according to any one of claims 1 to 15,
The mucoadhesive polymer is polysaccharide, acacia, agar, pectin, sodium alginate, calcium alginate, xanthan gum, tragacanth, carrageenan, polypeptide, casein, gelatin, vinyl, polyvinyl alcohol, povidone, carbomer, polyethylene A pharmaceutical composition comprising at least one of glycol, poloxamer and polyacrylic acid derivatives. The method according to any one of claims 1 to 15,
The mucoadhesive polymer is sodium carboxymethylcellulose, polyacrylic acid derivative, chitosan, hyaluronic acid, gellan gum, alginate, pectin, carrageenan, gelatin, acacia, gum tragacanth, xanthan gum, poloxamer, hydroxypropylmethylcellulose , Hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, hydroxyethylcellulose, ethylcellulose, polyvinyl alcohol, pyroxillin (pyroxylin), polyethylene oxide, and a pharmaceutical composition comprising at least one of povidone. The method according to any one of claims 1 to 15,
The mucoadhesive polymer is at least one of sodium alginate, hydroxypropylmethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose, a pharmaceutical composition. The method of claim 20,
The composition comprises 0.5% w/w to 10% w/w of mucoadhesive polymer, hydroxypropylmethylcellulose, hydroxyethylcellulose, or mixtures thereof. The method of claim 20,
The composition comprises 0.5% w/w to 10% w/w of mucoadhesive polymer, hydroxypropylcellulose, hydroxyethylcellulose, or mixtures thereof. The method according to any one of claims 1 to 22,
The pharmaceutical composition further comprising a healing adjuvant. The method of claim 23,
The healing aid is papain, D-panthenol, propolis, sunflower oil or calcium alginate, hyaluronic acid, chamomile, grapeseed oil, and one or more of Calendula officinalis, pharmaceutical composition. The method of claim 24,
The healing aid is D-panthenol, pharmaceutical composition. The method according to any one of claims 23 to 25,
The composition comprises 0.5% to 7% of a healing aid, a pharmaceutical composition. The method according to any one of claims 1 to 26,
The non-aqueous vehicle is caprylic capric triglyceride oil, diethylene glycol monoethyl ether, medium chain mono-diglyceride, castor oil, mineral oil, coconut oil, oleic acid, medium chain triglyceride, caprylocapro One macrogol-8 glyceride, propylene glycol, glycerin and polyethylene glycol derivatives, and at least one of polyethylene glycol, a pharmaceutical composition. The method of claim 27,
The pharmaceutical composition, wherein the non-aqueous vehicle is propylene glycol. The method of claim 27,
The non-aqueous vehicle is diethylene glycol monoethyl ether, pharmaceutical composition. The method of claim 27,
The non-aqueous vehicle is polyethylene glycol (PEG). The method of claim 27,
The pharmaceutical composition, wherein the non-aqueous vehicle is caprylocaproyl macrogol-8 glyceride. The method according to any one of claims 27, 28, 29, 30 or 31,
The pharmaceutical composition, wherein the composition comprises 0.5% w/w to 50% w/w of a non-aqueous vehicle. The method according to any one of claims 1 to 32,
Tocopherol in the alpha, gamma and beta forms; Ascorbic acid; Citric acid monohydrate; Ascorbyl palmitate; Butylated hydroxytoluene; Butylated hydroxyanisole; Erythorbic acid; Fumaric acid; Malic acid; Methionine; Monothioglycerol; Metabisulfite and sodium bisulfite; Propionic acid; Propyl gallate; Sodium ascorbate; Sodium formaldehyde sulfoxylate; Sodium sulfite; Sodium thiosulfate; Sulfur dioxide; The pharmaceutical composition further comprising an antioxidant selected from at least one of thymol and polyethylene glycol succinate of vitamin E. The method of claim 33,
The composition comprises 0.01% w/w to 1.0% w/w of an antioxidant. The method of claim 4,
The local local anesthetic is lidocaine hydrochloride; The anal dilator is diltiazem hydrochloride; The non-aqueous vehicle comprises at least one of propylene glycol, coconut oil, oleic acid, polyethylene glycol, diethylene glycol monoethyl ether, glycerin, medium chain triglyceride, caprylocaproyl macrogol-8 glyceride; The mucoadhesive polymer comprises at least one of sodium alginate, hydroxypropylmethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.